有机化学 ›› 2020, Vol. 40 ›› Issue (7): 1967-1974.DOI: 10.6023/cjoc201902036 上一篇    下一篇

所属专题: 陈茹玉先生诞辰100周年

研究论文

含苯并噻唑的4-氨基喹唑啉衍生物的合成及抗肿瘤活性研究

张路野a,b, 张洋a,b, 汪正捷a,b, 王涛a,b, 刘丽敏a,b, 刘秀娟a,b, 李二冬a,b, 宋攀攀a,b, 郑甲信a,b, 可钰a,b, 单丽红a,d, 刘宏民a,b,c,d, 张秋荣a,b,d   

  1. a 郑州大学药学院 郑州 450001;
    b 新药创制与药物安全性评价河南省协同创新中心 郑州 450001;
    c 省部共建食管癌防治国家重点实验室 郑州 450052;
    d 教育部药物制备关键技术重点实验室 郑州 450001
  • 收稿日期:2020-02-26 修回日期:2020-04-13 发布日期:2019-05-06
  • 通讯作者: 单丽红, 刘宏民, 张秋荣 E-mail:zqr409@yeah.net;shlh@zzu.edu.cn;liuhm@zzu.edu.cn
  • 基金资助:
    国家自然科学基金(No.U1904163)、蛋白关键研究(No.2018YFE0195100)和省部共建食管癌防治国家重点实验室资助的开放基金(No.K2020000X)资助项目.

Synthesis and Antitumor Activity of Novel 4-Aminoquinazoline Derivatives Containing Benzothiazole

Zhang Luyea,b, Zhang Yanga,b, Wang Zhengjiea,b, Wang Taoa,b, Liu Limina,b, Liu Xiujuana,b, Li Erdonga,b, Song Panpana,b, Zheng Jiaxina,b, Ke Yua,b, Shan Lihonga,d, Liu Hongmina,b,c,d, Zhang Qiuronga,b,d   

  1. a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001;
    b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001;
    c State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052;
    d Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou 450001
  • Received:2020-02-26 Revised:2020-04-13 Published:2019-05-06
  • Supported by:
    Project supported by the National Natural Science Foundation of China (No. U1904163) and the Key Research Program of Proteins (No. 2018YFE0195100) and the Openning Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment (No. K2020000X).

为了寻找高效低毒的抗肿瘤药物,设计并合成了一系列新型的含苯并噻唑结构的4-氨基喹唑啉类衍生物,并采用噻唑蓝(MTT)法测定了目标化合物对人乳腺癌细胞系(MCF-7)、人胃癌细胞系(MGC-803)、人前列腺癌细胞系(PC-3)和人高度分化的胃癌细胞系(HGC-27)四种肿瘤细胞的抗增殖活性.结果显示大部分化合物具有较好的抗肿瘤活性,其中2-((苯并[d]噻唑-2-基甲基)硫亚基)-N-(3-氯-4-氟苯基)-喹唑啉-4-胺(13n)对MCF-7、MGC-803、PC-3和HGC-27四种细胞显示出最好的抗增殖活性,IC50值分别为(6.01±0.54),(7.63±0.48),(6.16±0.34)和(7.59±0.62) μmol·L-1,其活性均优于阳性对照物吉非替尼.分子对接结果显示化合物13n能与表皮生长因子受体(EGFR)很好地结合,为抗肿瘤药物的研究提供了线索.

关键词: 苯并噻唑, 4-氨基喹唑啉, 合成, 抗肿瘤活性

In order to find efficient and low toxicity anti-tumor drugs, a series of novel 4-aminoquinazoline derivatives containing benzothiazole were designed and synthesized. And their antiproliferative activities against four human cancer cell lines[human breast cancer cell line (MCF-7), human gastric carcinoma cell line (MGC-803), human prostate cancer cell line (PC-3), human gastric carcinoma cell line (HGC-27)] were evaluated by using methyl thiazolyl tetrazolium (MTT) assay. The results showed that most compounds exhibited good antiproliferative activities against the four human tumor cell lines. Among them, 2-((benzo[d]thiazol-2-ylmethyl)thio)-N-(3-chloro-4-fluorophenyl)-quinazolin-4-amine (13n) showed the best antiproliferative activity against MCF-7, MGC 803, PC-3 and HGC-27 cancer cell lines, with IC50 values of (6.01±0.54), (7.63±0.48), (6.16±0.34), (7.59±0.62) μmol·L-1, respectively. Its activity was better than the positive control gefitinib. Molecular docking showed that compound 13n could bind well with epidermal growth factor receptor (EGFR). In a nutshell, this work provides clues to discover antitumor agent based on the quinazoline scaffold.

Key words: benzothiazole, 4-aminoquinazoline, synthesis, antiproliferative activity